Newborn infants are routinely screened for the presence of inherited metabolic disorders. These disorders are the consequence of a gene mutation which alters or inactivates a key enzyme in the metabolism of a nutrient such as a carbohydrate or amino acid. One of the most common of such disorders is galactosemia which occurs in 1 of every 8700 live births. Classical galactosemia is a potentially lethal disease caused by mutations which impair galactose-1-phosphate uridyl-transferase (GALT) (enzyme classification 2.7.7.12). This enzyme catalyzes the second step in the critical metabolic sequences which convert galactose to glucose. Since the newborn infant's principle nutritional energy source is lactose (disaccharide of glucose and galactose), this pathway is critical both for energy from glucose-1-phosphate oxidation and for uridyl diphosphate-galactose as a source for posttranslational galactosylation of membrane proteins in the rapidly growing infant.
Deficiency can lead to catastrophic events in the newborn with symptoms progressing from poor feeding, prolonged jaundice, bleeding diathesis and cataracts to E. coli sepsis and death. The simple exclusion of galactose from the newborn diet halts this toxic progression and is lifesaving. One may anticipate that the sooner in the newborn's life the diagnosis is suspected and the dietary change to sucrose-based (soy) formula is made, the better the short-term outcome in preventing neonatal death.
Long term outcome in children with galactosemia is more complex. Many older children have growth and developmental delays, verbal dyspraxia, and ovarian failure regardless of the age at which dietary intervention was accomplished. One of the factors determining outcome is the degree of GALT impairment. Following cloning and sequencing of the GALT gene, over 90 variations have been detected which produce different degrees of impairment. Some of these mutations produce partial but not total ablation of GALT enzyme activity.
At present, newborn screening is carried out for GALT using enzyme linked methods on blood samples obtained by heel stick and blotted on filter paper. This process measures enzyme activity in the red blood cell which is non-nucleated and possesses no protein synthesis capability. If the GALT enzyme is destabilized by a mutation or is inactivated by high environmental temperatures during transport of the sample, it will result in return of a positive galactosemic result even if clinically significant amounts of GALT are present. Follow-up screening by biochemical phenotyping and molecular genotyping are then required to characterize the positive screening result. In a recent study of 1.7 million newborns in Georgia, 2,463 were "positive", and 384 were determined to have impaired GALT producing a false positive rate of 84%. Of the 384 with abnormal GALT, 180 had clinically significant galactosemia, defined as GALT activity below 10% of control with classical galactosemia and these were placed on galactose-free diets.
From the foregoing it is evident that the present methodology of newborn screening has high sensitivity but low specificity in establishing the degree of GALT impairment in the infant. What is required is the ability to measure enzyme function as it exists within the individual.